1. Cinchona Alkaloids : Efficient Bifunctional Organocatalyts in Asymmetric Synthesis Antonin Clemenceau Frontiers in Chemical Synthesis PhD in J. Zhu Group 23.05.14

2. Questions : What is a pseudo-enantiomer ? What could be the future or the other possibilities of this organocatalyst? 2

3. Plan : Introduction Organocatalysis: Concepts and Principle Organocatalysts Cinchona Alkaloids Presentation History Other Potential Examples 3

4. Introduction Concept borns in the late 1990s Before only enzymes and metal-catalyst were used for asymmetric catalysis Another powerful tool for the Modern Organic Chemistry Explosion of this field during this century Organocatalysis 4

5. Organocatalysis: Concepts and principle Principle Definition : The use of small organic molecules to catalyse asymmetric transformation First example of asymmetric organic synthesis was reported with proline catalyst in 1971 by two industrial research groups Advantage: - Non-toxic, environmentally friendly - Low cost - Robust - Metal-free reaction Creation of a new C-C or C-heteroatom bond controlled by the organocatalyst ===> Induction of chirality 5

6. Organocalysts 6

7. Nomenclature Cinchona Alkaloids Quinine isolated by Pelletier in 1820 First used for a resolution of a racemate in 1853 by Pasteur Quinine and derivatives were recognized as antimalarial agent First Total Synthesis in 1944 by Woodward and Doering Used as potential ligand for Lewis acidic metal at the beginning Considered as pseudo-enantiomers because -The stereogenic centers (C8, C9) have the opposite absolute configuration -The centers in the quinuclidine fragment (C3, C4) are identical Ref: T. Marcelli, J. H. van Maarseveen, H. Hiemstra Angew. Chem. Int. Ed. 2006, 45, 7496 – 7504 Quinquina Tree 7

8. Cinchona Alkaloids Bifunctional Catalyst Ref: A. G. Doyle, E. N. Jacobsen Chem. Rev. 2007, 107, 5713 – 5743 J. Alemán, A. Parra, H. Jiang, K. A. Jørgensen Chem. Eur. J. 2011, 17, 6890 – 6899 J. -W. Xie, W. Chem, R. Li, M. Zeng, W. Du, L. Yue, Y. -C. Chen, Y. Wu, J. Zhu, J. -G. Deng Angew. Chem. Int. Ed. 2007, 46, 389 –392 Easily tunable moiety 8

9. 1981: Quinine Ref: H. Hiemstra, H. Wynberg J. Am. Chem. Soc. 1981, 103, 417. Enantioselective conjugate addition of aromatic thiols to conjugated cycloalkenones First example of Cinchona Alkaloid as Organocatalyst 9

10. 1981: Suggested Mechanism Ref: H. Hiemstra, H. Wynberg J. Am. Chem. Soc. 1981, 103, 417. 10

11. 1999 :  -Isocupreine Ref: Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeyama J. Am. Chem. Soc. 1999, 121, 10219-10220  -Isocupreine Cagelike structure Conformationally rigid No pseudoenantiomer of the  -isocupreine easily accessible Asymmetric Baylis−Hillman Reaction Reaction between 1,1,1,3,3,3-hexafluoroisopropyl (HFIP) acrylate and aldehydes 11

12. 1999 : Proposed Reaction Mechanism Ref: Y. Iwabuchi, M. Nakatani, N. Yokoyama, S. Hatakeyama J. Am. Chem. Soc. 1999, 121, 10219-10220 See also: G. Masson, J. Zhu, C. Housseman Angew. Chem. Int. Ed. 2007, 46, 4614 – 4628 Syn diastereomers are produced from the aldol reaction Steric constraints of C unfavoured the  elimination 12

13. 2004 : Cupreine and Isocupreine Ref: H. Li, Y. Wang, L. Tang, L. Deng J. Am. Chem. Soc. 2004, 126, 9906-9907 Enantioselective Conjugate Addition of Malonate and  -Ketoester to Nitroalkane 13

14. 2005 : Thiourea Cinchona Alkaloids Ref: J. Ye, D. J. Dixon, P. S. Hynes Chem. Commun. 2005,4481 S. H. McCooey, S. J. Connon Angew. Chem. Int. Ed. 2005, 44, 6367 B. Vakulya, S. Varga, A. Csámpai, T. Soós Org. Lett., 2005, 7, 1967-1969 M. S. Taylor, E. N. Jacobsen Angew. Chem. Int. Ed. 2006, 45, 1520 – 1543 Simultaneous donation of two hydrogens Electrophile activation as enzymes system Strong and directional H-bonds favour asymmetric transformation 14

15. 2005 : Thiourea Cinchona Alkaloids Ref: J. Ye, D. J. Dixon, P. S. Hynes Chem. Commun. 2005,4481 S. H. McCooey, S. J. Connon Angew. Chem. Int. Ed. 2005, 44, 6367 B. Vakulya, S. Varga, A. Csámpai, T. Soós Org. Lett., 2005, 7, 1967-1969 Enantioselective Conjugate Addition 15

16. 2006 : C6’- Thiourea Cinchona Alkaloids Ref: T. Marcelli, R. N. S. van der Haas, J. H. van Maarseveen, H. Hiemstra Angew. Chem. Int. Ed. 2006, 45, 929 –931 Asymmetric Henry reaction between aldehydes and nitromethane Switch of the H-bond donor C9 to C6’ 16

17. 2007 : Amino Cinchona Alkaloids Ref: P. Melchiorre Angew. Chem. Int. Ed. 2012, 51, 9748 – 9770 L. Jiang, Y. -C. Chen Catal. Sci. Technol. 2011,1, 354-365 S. Bertelsen, K. A. Jørgensen Chem. Soc. Rev., 2009, 38, 2178–2189 Activation mode: Secondary amine vs Primary amine 17

18. 2007 : Amino Cinchona Alkaloids Ref: P. Melchiorre Angew. Chem. Int. Ed. 2012, 51, 9748 – 9770 L. Jiang, Y. -C. Chen Catal. Sci. Technol. 2011,1, 354-365 S. Bertelsen, K. A. Jørgensen Chem. Soc. Rev., 2009, 38, 2178–2189 Activation mode 18

19. 2007 : Amino Cinchona Alkaloids Ref: P. Melchiorre Angew. Chem. Int. Ed. 2012, 51, 9748 – 9770 L. Jiang, Y. -C. Chen Catal. Sci. Technol. 2011,1, 354-365 S. Bertelsen, K. A. Jørgensen Chem. Soc. Rev., 2009, 38, 2178–2189 Activation mode 19

20. Ref: J.-W. Xie, W. Chen, R. Li, M. Zeng, W. Du, L. Yue, Y. –C. Chen, Y. Wu, J. Zhu, J. –G. Deng Angew. Chem. Int. Ed. 2007, 46, 389 –392 W. Chen, W. Du, Y. –Z. Duan, Y. Wu, S.-Y. Yang, Y.- C. Chen Angew. Chem. Int. Ed. 2007, 46, 7667 –7670 The same year, 2 other groups published organocatalytic reaction with Amino Cinchona Alkaloids: S. H. McCooey, S. J. Connon Org. Lett. 2007, 9, 599 – 602. G. Bartoli, M. Bosco, A. Carlone, F. Pesciaioli, L. Sambri, P. Melchiorre Org. Lett. 2007, 9, 1403 – 1405. 2007 : Amino Cinchona Alkaloids Iminium Activation mode 20

21. Ref: J. P. Malerich, K. Hagihara, V. H. Rawal, J. Am. Chem. Soc. 2008, 130, 14416. J. Alemán, A. Parra, H. Jiang, K. A. Jørgensen Chem. Eur. J. 2011, 17, 6890 – 6899 2008 : Squaramide Cinchona Alkaloids Difference with thiourea: Asymmetric conjugate addition of dicarbonyle to nitroalkene 21

22. Other Potential Application Over the years Conjugate Addition is the most common transformation performs with Cinchona Alkaloids Other potential transformation possible? 22

23. Other Potential Application Ref.: Y. -Q. Wang, J. Song, R. Hong, H. Li, L. Deng J. Am. Chem. Soc. 2006, 128, 8156 Asymmetric Friedel-Crafts Reaction of Indoles with Imines 23

24. Other Potential Application Ref.: Y. Wang, H. Li, Y. -Q. Wang, Y. Lui, B. M. Foxman, L. Deng J. Am. Chem. Soc. 2007, 129, 6364-6365 Asymmetric Diels−Alder Reactions 24

25. Other Potential Application Asymmetric Diels−Alder Reactions Ref.: Y. Wang, H. Li, Y. -Q. Wang, Y. Lui, B. M. Foxman, L. Deng J. Am. Chem. Soc. 2007, 129, 6364-6365 25

26. Ref: P. Kwiatkowski, T. D. Beeson, J. C. Conrad, D. W. C. MacMillan J. Am. Chem. Soc. 2011, 133, 1738–1741 Other Potential Application Enantioselective α-Fluorination of Cyclic Ketones First highly enantioselective fluoration using Organocatalysis Cinchona Alkaloids give the best result Enamine activation mode 26

27. Ref: T. Buyck, Q. Wang, J. Zhu Angew. Chem. Int. Ed. 2013, 52, 12714 – 12718 Enantioselective Michael Addition of α-Aryl-α-Isocyanoacetates to Vinyl Selenone Other Potential Application …Toward Total Synthesis 27

28. Other Potential Application Ref: F. Manoni, S. J. Connon Angew. Chem. Int. Ed. 2014, 53, 2628 –2632 Asymmetric Tamura cycloadditions 28

29. Suggested Mechanism Ref: X. Yin, Y. Zheng, X. Feng, K. Jiang, X. -Z. Wei, N. Gao, Y. –C. Chen Angew. Chem. Int. Ed. 2014, 53, asap 29 Asymmetric Tamura cycloadditions

30. Other Potential Application Ref: X. Yin, Y. Zheng, X. Feng, K. Jiang, X. -Z. Wei, N. Gao, Y. –C. Chen Angew. Chem. Int. Ed. 2014, 53, asap Asymmetric [5+3] formal cycloadditions of cyclic enones with 3-vinyl-1,2-benzoisothiazole-1,1-dioxides 30

31. Suggested Mechanism *The stereochemistry of this example is not explain in the paper Ref: X. Yin, Y. Zheng, X. Feng, K. Jiang, X. -Z. Wei, N. Gao, Y. –C. Chen Angew. Chem. Int. Ed. 2014, 53, asap 31

32. Conclusion 32 -Easily avalaible & tunable -Various way of substrate activation -Enantioselective control -Catalytic process -Environmentally friendly Still some progress can be possible Other organocatalyts or Metal-catalyst are competitive

33. Thanks for your attention

34. Questions : What is a pseudo-enantiomer ? What could be the future or the other possibilities of this organocatalyst? 2

35. Combined Metal-Catalyzed and Organocatalysis